Bladder Cancer Treatment (PDQ®) 2/2 —Health Professional Version - National Cancer Institute

Bladder Cancer Treatment (PDQ®)—Health Professional Version - National Cancer Institute

Bladder Cancer Treatment (PDQ®)–Health Professional Version

Stages II and III Bladder Cancer Treatment

In This Section

• Standard Treatment Options for Stages II and III Bladder Cancer
  • Radical cystectomy
  • Neoadjuvant combination chemotherapy followed by radical cystectomy
  • EBRT with or without concomitant chemotherapy
  • Segmental cystectomy (in selected patients)
  • TUR with fulguration (in selected patients)
• Current Clinical Trials

Standard Treatment Options for Stages II and III Bladder Cancer

Standard treatment options for stage II bladder cancer and stage III bladder cancerinclude the following:

1. Radical cystectomy.
2. Neoadjuvant combination chemotherapy followed by radical cystectomy.
3. External-beam radiation therapy (EBRT) with or without concomitant chemotherapy.
4. Segmental cystectomy (in selected patients).
5. Transurethral resection (TUR) with fulguration (in selected patients).

The most common treatments for muscle-invasive bladder cancer are radical cystectomy and radiation therapy. There is no strong evidence from randomized controlled trials to determine whether surgery or radiation therapy is more effective. There is strong evidence that both therapies become more effective when combined with chemotherapy. The treatments with the highest level of evidence supporting their effectiveness are radical cystectomy preceded by multiagent cisplatin-based chemotherapy and radiation therapy with concomitant chemotherapy.

Radical cystectomy

Radical cystectomy is a standard treatment option for stage II and stage III bladder cancer, and its effectiveness at prolonging survival increases if it is preceded by cisplatin-based multiagent chemotherapy.[1-4] Radical cystectomy is accompanied by pelvic lymph node dissection and includes removal of the bladder, perivesical tissues, prostate, and seminal vesicles in men and removal of the uterus, fallopian tubes, ovaries, anterior vaginal wall, and urethra in women.[5-8] Studies of outcomes after radical cystectomy report increased survival in patients who had more, rather than fewer, lymph nodes resected; whether this represents a therapeutic benefit of resecting additional nodes or stage migration is unknown.[9] There are no randomized controlled trials evaluating the therapeutic benefit of lymph node dissection in this setting.

Radical cystectomy is a major operation with a perioperative mortality rate of 2% to 3% when performed at centers of excellence.[6-8] Postoperative complications include ileus. Most men have erectile dysfunction after radical cystectomy; sexual dysfunction after this operation is also common in women.[10-12]

One study of 27 women who underwent radical cystectomy reported diminished ability to have orgasm in 45%, decreased lubrication in 41%, decreased sexual desire in 37%, and pain with vaginal intercourse in 22%. Fewer than one-half were able to have successful vaginal intercourse and most reported decreased satisfaction with their sexual lives after surgery.[12] Studies suggest that radical cystectomy with preservation of sexual function can be performed in some men. In addition, new forms of urinary diversion can obviate the need for an external urinary appliance.[13-16]

In a retrospective analysis from a single institution, elderly patients (≥70 years) in good general health were found to have clinical and functional results after radical cystectomy similar to younger patients.[17]

After radical cystectomy, however, an approximate 30% to 40% risk of recurrence still exists for patients with muscle-invasive disease, even at centers of excellence.[6-8] Five-year overall survival (OS) has generally been reported to be in the range of 50% to 60% but varies by stage.[4] The addition of preoperative radiation therapy to radical cystectomy did not result in any survival advantage when compared with radical cystectomy alone in a prospective randomized trial.[18]

Neoadjuvant combination chemotherapy followed by radical cystectomy

Because bladder cancer commonly recurs with distant metastases, systemic chemotherapy administered before or after cystectomy has been evaluated as a means of improving outcome. Administration of chemotherapy before cystectomy (i.e., neoadjuvant chemotherapy) may be preferable to postoperative treatment because tumor downstaging from chemotherapy may enhance resectability; occult metastatic disease may be treated as early as possible; and chemotherapy may be better tolerated. Currently, the body of evidence supporting preoperative chemotherapy is much stronger than the evidence supporting postoperative chemotherapy.

Evidence (neoadjuvant combination chemotherapy followed by radical cystectomy):

1. A controlled trial of preoperative chemotherapy conducted by the Medical Research Council and the European Organization for Research and Treatment of Cancer randomly assigned 976 patients with locally advanced (T3 or T4a) or high-grade muscle-invasive (T2) bladder cancer to undergo either definitive treatment immediately or definitive treatment preceded by three cycles of neoadjuvant cisplatin, vinblastine, and methotrexate.[19,20] In this study, definitive treatment consisted of radical cystectomy (n = 428), radiation therapy (n = 403), or preoperative radiation therapy followed by radical cystectomy (n = 66).
   • At a median follow-up of 8.0 years for patients still alive, OS was significantly greater in the arm randomly assigned to receive neoadjuvant chemotherapy (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.72–0.99; P = .037). The survival benefit from neoadjuvant chemotherapy compared with definitive treatment alone conferred a 6% absolute increase in the likelihood of being alive at 3 years (56% vs. 50%), 5 years (49% vs. 43%), and 10 years (36% vs. 30%).[20][Level of evidence: 1iiA]
2. A randomized study conducted by the Southwest Oncology Group compared three cycles of neoadjuvant cisplatin, methotrexate, vinblastine, and doxorubicin administered before cystectomy with cystectomy alone in 317 patients with stage T2 to stage T4a bladder cancer.[21]
   • The study showed that 5-year survival was 57% in the group that received neoadjuvant chemotherapy and 43% in the group treated with cystectomy alone, which is a difference of borderline statistical significance (two-sided Pvalue = .06 by stratified log-rank test).
   • No deaths were associated with neoadjuvant chemotherapy, and there was no difference in the rate or severity of postoperative complications in patients who received immediate surgery and in those who received preoperative chemotherapy. Cystectomy was performed as planned for 82% of patients assigned to preoperative chemotherapy and 81% of those assigned to cystectomy alone. This study provided evidence that preoperative chemotherapy does not prevent patients from undergoing cystectomy and does not increase the risk of perioperative complications.
   • Thirty-eight percent of patients who received neoadjuvant chemotherapy had a pathologic complete response at the time of surgery, and 85% of those achieving a pathologic complete response were alive at 5 years.
3. A meta-analysis of ten randomized trials of neoadjuvant chemotherapy, including updated data for 2,688 individual patients, showed that cisplatin-based combination chemotherapy was associated with a significant 13% relative reduction in the risk of death and resulted in an improvement in 5-year survival from 45% to 50% (P = .016). Neoadjuvant single-agent cisplatin was not associated with any survival benefit in the meta-analysis.[2]
4. A subsequent meta-analysis evaluated a nearly identical body of data (11 randomized controlled trials enrolling a total of 2,605 patients) and reached similar conclusions. When the analysis was limited to the eight trials that used multiagent, cisplatin-based chemotherapy, neoadjuvant chemotherapy compared with cystectomy alone was associated with a 6.5% absolute benefit in 5-year OS (56.5% vs. 50%; P = .006).[4]

Most patients included in these studies received cisplatin, methotrexate, and vinblastine with or without doxorubicin. It is not known whether the doublet regimen of cisplatin plus gemcitabine offers any benefit when administered in the preoperative setting, nor is there any evidence of benefit for carboplatin-based chemotherapy regimens.

On the basis of these findings, preoperative cisplatin-based combination chemotherapy followed by radical cystectomy represents a standard therapeutic option for patients with muscle-invasive bladder cancer who are fit for chemotherapy and for whom the priority is to maximize survival.

EBRT with or without concomitant chemotherapy

Definitive radiation therapy is a standard option that yields a 5-year survival of approximately 30% to 40%.[22] When radiation therapy and chemotherapy are administered concomitantly, the results are better. However, while the addition of chemotherapy to radiation therapy has been shown to reduce local relapse rates, it has not been shown to result in increased survival, decreased mortality, or improved quality of life.

Most protocols for bladder preservation that use combined chemotherapy and radiation therapy have followed a relatively complex algorithm. After the initial stage TUR of the bladder tumor, patients undergo a repeat TUR to maximally resect the tumor. The patient is then treated with synchronous chemoradiation therapy to a dose of roughly 40 Gy followed by a repeat cystoscopy with biopsies to assess for residual cancer. If residual cancer is detected histopathologically, then the chemoradiation therapy is judged to have failed and the patient is advised to undergo a radical cystectomy. If the biopsies at 40 Gy are benign, then chemoradiation therapy is completed to a dose of about 65 Gy.

With definitive radiation therapy, best results are seen in patients with solitary lesions and without carcinoma in situ or hydronephrosis

After radiation therapy, approximately 50% of patients have dysuria and urinary frequency during treatment, which resolves several weeks after treatment, and 15% report acute toxic effects of the bowel.

Randomized trials that directly compare the bladder-preserving chemoradiation therapy approach with radical cystectomy have not been performed; the relative effectiveness of these two treatments is thus unknown.

Evidence (EBRT with or without concomitant chemotherapy):

TUR followed by chemoradiation therapy

1. A multicenter phase III trial randomly assigned 360 patients with muscle-invasive bladder cancer to radiation therapy with or without synchronous chemotherapy using fluorouracil and mitomycin C.[22]
   • Two-year locoregional disease-free survival was higher in the chemoradiation therapy group (67% vs. 54%; HR, 0.68; 95% CI, 0.48–0.96; P = .03). Five-year OS was 48% in the chemoradiation therapy group and 35% in the radiation therapy group, but the difference was not statistically significant (P = .16).
2. Similarly, synchronous chemoradiation therapy using other chemotherapy regimens, such as cisplatin alone or combined with fluorouracil, have reported 5-year OS rates of 50% to 60% and survival with an intact bladder in 40% to 45% of patients, figures that are higher than has generally been reported in studies of radiation therapy alone.[23]

TUR followed by chemoradiation therapy

1. In some nonrandomized studies, 50% or more of the patients who underwent bladder-preserving therapy (i.e., initial TUR of as much tumor as possible followed by concurrent chemoradiation therapy) were alive at 5 years, and 75% of those survivors had an intact bladder.[24-26]

Radiation therapy and chemotherapy

1. A randomized controlled trial randomly assigned 99 patients with T2 to T4b urothelial carcinoma of the bladder to radiation therapy with or without three 14-day cycles of cisplatin (100 mg/m2 on day 1). Patients and their physicians chose whether the radiation therapy was definitive or administered as precystectomy treatment. The pelvic relapse rate was reduced (multivariable regression model HR, 0.50; 90% CI, 0.29–0.86; P = .036), but there was no difference in the occurrence of distant metastases or OS. The reduction in pelvic relapse was similar in patients who received definitive radiation therapy and precystectomy radiation therapy.[27]

Neoadjuvant chemotherapy followed by chemoradiation therapy

1. In a phase III study (RTOG-8903Exit Disclaimer), the Radiation Therapy Oncology Group evaluated the potential benefit of adding two cycles of neoadjuvant methotrexate, cisplatin, and vinblastine before concurrent cisplatin and radiation therapy. Neoadjuvant chemotherapy was associated with increased hematologic toxic effects and yielded no improvement in response rate, freedom from distant metastases, or OS compared with chemoradiation therapy alone.[28]

Segmental cystectomy (in selected patients)

Segmental cystectomy is appropriate only in very selected patients.[1] There are no randomized controlled trials comparing segmental cystectomy with radical cystectomy. Only patients with adenocarcinomas of the urachus are routinely treated with segmental cystectomy. These tumors typically are mucinous adenocarcinomas occurring at the dome of the bladder and are treated with an en bloc resection of the bladder dome and urachal remnant, including the umbilicus.[29-32]

TUR with fulguration (in selected patients)

Stage II bladder cancer may be controlled in some patients by TUR, but more aggressive forms of treatment are often dictated by recurrent tumor or by the large size, multiple foci, or undifferentiated grade of the neoplasm.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

1. Richie JP: Surgery for invasive bladder cancer. Hematol Oncol Clin North Am 6 (1): 129-45, 1992. [PUBMED Abstract]
2. Advanced Bladder Cancer Meta-analysis Collaboration: Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis. Lancet 361 (9373): 1927-34, 2003. [PUBMED Abstract]
3. Sherif A, Holmberg L, Rintala E, et al.: Neoadjuvant cisplatinum based combination chemotherapy in patients with invasive bladder cancer: a combined analysis of two Nordic studies. Eur Urol 45 (3): 297-303, 2004. [PUBMED Abstract]
4. Winquist E, Kirchner TS, Segal R, et al.: Neoadjuvant chemotherapy for transitional cell carcinoma of the bladder: a systematic review and meta-analysis. J Urol 171 (2 Pt 1): 561-9, 2004. [PUBMED Abstract]
5. Olsson CA: Management of invasive carcinoma of the bladder. In: deKernion JB, Paulson DF, eds.: Genitourinary Cancer Management. Philadelphia, Pa: Lea and Febiger, 1987, pp 59-94.
6. Stein JP, Lieskovsky G, Cote R, et al.: Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol 19 (3): 666-75, 2001. [PUBMED Abstract]
7. Madersbacher S, Hochreiter W, Burkhard F, et al.: Radical cystectomy for bladder cancer today--a homogeneous series without neoadjuvant therapy. J Clin Oncol 21 (4): 690-6, 2003. [PUBMED Abstract]
8. Manoharan M, Ayyathurai R, Soloway MS: Radical cystectomy for urothelial carcinoma of the bladder: an analysis of perioperative and survival outcome. BJU Int 104 (9): 1227-32, 2009. [PUBMED Abstract]
9. Ather MH, Fatima S, Sinanoglu O: Extent of lymphadenectomy in radical cystectomy for bladder cancer. World J Surg Oncol 3: 43, 2005. [PUBMED Abstract]
10. Hart S, Skinner EC, Meyerowitz BE, et al.: Quality of life after radical cystectomy for bladder cancer in patients with an ileal conduit, cutaneous or urethral kock pouch. J Urol 162 (1): 77-81, 1999. [PUBMED Abstract]
11. Miyao N, Adachi H, Sato Y, et al.: Recovery of sexual function after nerve-sparing radical prostatectomy or cystectomy. Int J Urol 8 (4): 158-64, 2001. [PUBMED Abstract]
12. Zippe CD, Raina R, Shah AD, et al.: Female sexual dysfunction after radical cystectomy: a new outcome measure. Urology 63 (6): 1153-7, 2004. [PUBMED Abstract]
13. Brendler CB, Steinberg GD, Marshall FF, et al.: Local recurrence and survival following nerve-sparing radical cystoprostatectomy. J Urol 144 (5): 1137-40; discussion 1140-1, 1990. [PUBMED Abstract]
14. Skinner DG, Boyd SD, Lieskovsky G: Clinical experience with the Kock continent ileal reservoir for urinary diversion. J Urol 132 (6): 1101-7, 1984. [PUBMED Abstract]
15. Fowler JE: Continent urinary reservoirs and bladder substitutes in the adult: part I. Monographs in Urology 8 (2): 1987.
16. Fowler JE: Continent urinary reservoirs and bladder substitutes in the adult: part II. Monographs in Urology 8 (3): 1987.
17. Figueroa AJ, Stein JP, Dickinson M, et al.: Radical cystectomy for elderly patients with bladder carcinoma: an updated experience with 404 patients. Cancer 83 (1): 141-7, 1998. [PUBMED Abstract]
18. Smith JA Jr, Crawford ED, Paradelo JC, et al.: Treatment of advanced bladder cancer with combined preoperative irradiation and radical cystectomy versus radical cystectomy alone: a phase III intergroup study. J Urol 157 (3): 805-7; discussion 807-8, 1997. [PUBMED Abstract]
19. Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: a randomised controlled trial. International collaboration of trialists. Lancet 354 (9178): 533-40, 1999. [PUBMED Abstract]
20. Griffiths G, Hall R, Sylvester R, et al.: International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J Clin Oncol 29 (16): 2171-7, 2011. [PUBMED Abstract]
21. Grossman HB, Natale RB, Tangen CM, et al.: Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 349 (9): 859-66, 2003. [PUBMED Abstract]
22. James ND, Hussain SA, Hall E, et al.: Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med 366 (16): 1477-88, 2012. [PUBMED Abstract]
23. Efstathiou JA, Zietman AL, Kaufman DS, et al.: Bladder-sparing approaches to invasive disease. World J Urol 24 (5): 517-29, 2006. [PUBMED Abstract]
24. Kachnic LA, Kaufman DS, Heney NM, et al.: Bladder preservation by combined modality therapy for invasive bladder cancer. J Clin Oncol 15 (3): 1022-9, 1997. [PUBMED Abstract]
25. Housset M, Maulard C, Chretien Y, et al.: Combined radiation and chemotherapy for invasive transitional-cell carcinoma of the bladder: a prospective study. J Clin Oncol 11 (11): 2150-7, 1993. [PUBMED Abstract]
26. Rödel C, Grabenbauer GG, Kühn R, et al.: Combined-modality treatment and selective organ preservation in invasive bladder cancer: long-term results. J Clin Oncol 20 (14): 3061-71, 2002. [PUBMED Abstract]
27. Coppin CM, Gospodarowicz MK, James K, et al.: Improved local control of invasive bladder cancer by concurrent cisplatin and preoperative or definitive radiation. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 14 (11): 2901-7, 1996. [PUBMED Abstract]
28. Shipley WU, Winter KA, Kaufman DS, et al.: Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03. J Clin Oncol 16 (11): 3576-83, 1998. [PUBMED Abstract]
29. Ashley RA, Inman BA, Sebo TJ, et al.: Urachal carcinoma: clinicopathologic features and long-term outcomes of an aggressive malignancy. Cancer 107 (4): 712-20, 2006. [PUBMED Abstract]
30. Siefker-Radtke A: Urachal carcinoma: surgical and chemotherapeutic options. Expert Rev Anticancer Ther 6 (12): 1715-21, 2006. [PUBMED Abstract]
31. Herr HW, Bochner BH, Sharp D, et al.: Urachal carcinoma: contemporary surgical outcomes. J Urol 178 (1): 74-8; discussion 78, 2007. [PUBMED Abstract]
32. Bruins HM, Visser O, Ploeg M, et al.: The clinical epidemiology of urachal carcinoma: results of a large, population based study. J Urol 188 (4): 1102-7, 2012. [PUBMED Abstract]

Stage IV Bladder Cancer Treatment

In This Section

• Standard Treatment Options for Stage IV Bladder Cancer
  • Standard treatment options for patients with T4b, N0, M0 disease
  • Standard treatment options for patients with any T, any N, M1 disease
• Treatment Options Under Clinical Evaluation for Patients With Any T, Any N, M1 Disease
• Current Clinical Trials

Only a small fraction of patients with stage IV bladder cancer can be cured and for many patients, the emphasis is on palliation of symptoms. The potential for cure is restricted to patients with stage IV disease with involvement of pelvic organs by direct extension or metastases to regional lymph nodes.[1]

Standard Treatment Options for Stage IV Bladder Cancer

Standard treatment options for patients with T4b, N0, M0 disease

Treatment options for patients with T4b, N0, M0 disease include the following:

1. Chemotherapy alone.
2. Radical cystectomy.
3. Radical cystectomy followed by chemotherapy.
4. Radical cystectomy alone.
5. External-beam radiation therapy (EBRT) with or without concomitant chemotherapy.
6. Urinary diversion or cystectomy for palliation.

Chemotherapy alone

Cisplatin-based combination chemotherapy regimens are the standard of care for stage IV bladder cancer.[2-6] The only chemotherapy regimens that have been shown to result in longer survival in randomized controlled trials are methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC); high-dose MVAC; and cisplatin, methotrexate, and vinblastine (CMV). Gemcitabine plus cisplatin (GC) was compared with MVAC in a randomized controlled trial and no difference in response rate or survival was reported. Of note, patients with good performance status and lymph node-only disease have a low but significant rate of achieving a durable complete remission with MVAC or GC. In the large, randomized, controlled trial that compared MVAC with GC, for example, 5-year overall survival (OS) in patients with lymph node-only disease was 20.9%.[7]

Single-agent cisplatin and multiagent regimens that do not include cisplatin have never been shown to improve survival in a randomized controlled trial. For patients who are not candidates for cisplatin-based multiagent chemotherapy regimens, there is no regimen that has been shown to prolong survival; however, many regimens have demonstrated radiologically measurable responses.

These include carboplatin plus paclitaxel,[8] carboplatin plus gemcitabine,[9-11] paclitaxel plus gemcitabine,[12-14] single-agent gemcitabine,[15,16] and single-agent paclitaxel.[17-19] Regimens of carboplatin, methotrexate, and vinblastine; carboplatin, epirubicin, methotrexate, and vinblastine; and paclitaxel, gemcitabine, and carboplatin have been studied but are not widely used.[20-23]

Evidence (chemotherapy alone):

1. Results from a randomized controlled trial that compared MVAC with docetaxel plus cisplatin in 220 patients reported that MVAC was associated with longer OS (median survival, 14.2 months vs. 9.3 months; P = .026).[24]
2. A randomized trial that compared MVAC with cisplatin, cyclophosphamide, and doxorubicin demonstrated improved response and median survival rates (48 weeks vs. 36 weeks; P = .003) with the MVAC regimen.[25]
3. Results from a randomized trial that compared MVAC with single-agent cisplatin in advanced bladder cancer also showed a significant advantage with MVAC in both response rate and median survival (12.5 months vs. 8.2 months; P = .002).[26]
4. A multicenter randomized controlled trial compared CMV with methotrexate plus vinblastine without cisplatin in 214 patients. The relative risk of dying was 0.68 (95% confidence interval [CI], 0.51–0.90; P = .0065) in favor of CMV. The median survival was 7 months with CMV and 4.5 months with methotrexate plus vinblastine.[27]
5. The European Organisation for Research and Treatment of Cancer (EORTC) conducted another randomized trial that studied 263 patients with advanced bladder cancer and evaluated the efficacy of a high-dose intensity MVAC regimen administered every 2 weeks with granulocyte colony-stimulating factor (G-CSF) versus a classic MVAC regimen administered every 4 weeks.[28]
   • Although there was no significant difference in OS at a median follow-up of 3.2 years (hazard ratio [HR], 0.80; 95% CI, 0.60–1.06; P = .122), an update at a median follow-up of 7.3 years reported that the high-dose intensity MVAC regimen was associated with improved OS (HR, 0.76; 95% CI, 0.58–0.99; P = .042), with a 5-year survival rate of 22% compared with 14% in patients treated with the classic MVAC regimen.
   • The high-dose intensity MVAC regimen was also associated with higher response rates (72% vs. 58%; P = .016), improved median progression-free survival (PFS) (9.5 months vs. 8.1 months; P = .017), and decreased neutropenic fever (10% vs. 26%; P < .001), although only 19% of patients treated with a classic MVAC regimen ever received G-CSF.[28][Level of evidence: 1iiA] An imbalance in baseline prognostic factors (i.e., visceral metastases were found in 37 patients randomly assigned to the high-dose MVAC regimen and 47 patients assigned to the classic MVAC regimen) may account, in part, for these results.
6. Gemcitabine plus cisplatin.
   • In a multicenter, randomized, phase III trial that compared GC with the MVAC regimen in 405 patients with advanced or metastatic bladder cancer, GC yielded response rates, time-to-progression, and OS (HR, 1.04; 95% CI, 0.82–1.32; P = .75) similar to MVAC, but GC had a better safety profile and was better tolerated than MVAC.
   • Although this study was not designed to show the equivalence of the two regimens, the similar efficacy and reduced toxic effects of GC make it a reasonable alternative in patients who may not tolerate the MVAC regimen.[29][Level of evidence: 1iiA]

Radical cystectomy

Patients with stage IV disease with involvement of pelvic organs by direct extension or metastases to regional lymph nodes may undergo radical cystectomy with pelvic lymph node dissection.[30-32] The extent of lymph node dissection during cystectomy is controversial [30] because there are no data from prospective trials demonstrating improved outcomes with lymph node dissection. Because T4b tumors cannot generally be completely resected and because lymph node metastases usually signal distant micrometastases, patients with locally advanced bladder cancer are usually given chemotherapy before surgery with the goal of facilitating resection and eliminating micrometastatic disease. Although there are data supporting preoperative chemotherapy for clinical stage II and stage III disease, patients with stage IV disease were excluded from most clinical trials investigating the role or preoperative chemotherapy.

External-beam radiation therapy (EBRT) with or without concomitant chemotherapy

Definitive radiation therapy with or without concurrent chemotherapy, evaluated mainly in patients with locally advanced (T2–T4) disease, appears to have minimal curative potential in patients with regional lymph node metastases.[33,34] Patients with evidence of lymph node metastases have generally been excluded from phase III trials of radiation therapy.[35,36]

Urinary diversion or cystectomy for palliation

Urinary diversion may be indicated, not only for palliation of urinary symptoms but also for preservation of renal function in candidates for chemotherapy.

Standard treatment options for patients with any T, any N, M1 disease

Standard treatment options for patients with any T, any N, M1 disease include the following:

1. Chemotherapy alone or as an adjunct to local treatment.
2. Immunotherapy.
3. EBRT for palliation.
4. Urinary diversion or cystectomy for palliation.

Chemotherapy alone or as an adjunct to local treatment

Cisplatin-based combination chemotherapy regimens are the standard of care for stage IV bladder cancer.[2-6] The only chemotherapy regimens that have been shown to result in longer survival in randomized controlled trials are MVAC, high-dose MVAC, and CMV. GC was compared with MVAC in a randomized controlled trial and no difference in response rate or survival was reported. Of note, patients with good performance status and lymph node-only disease have a low but significant rate of achieving a durable complete remission with MVAC or GC. In the large, randomized, controlled trial comparing MVAC with GC, for example, 5-year OS in patients with lymph node-only disease was 20.9%.[7]

Single-agent cisplatin and multiagent regimens that do not include cisplatin have never been shown to improve survival in a randomized controlled trial. For patients who are not candidates for cisplatin-based multiagent chemotherapy regimens, there is no regimen that has been shown to prolong survival; however, many regimens have demonstrated radiologically measurable responses.

These include carboplatin plus paclitaxel,[8] carboplatin plus gemcitabine,[9-11] paclitaxel plus gemcitabine,[12-14] single-agent gemcitabine,[15,16] and single-agent paclitaxel.[17-19] The regimens of carboplatin, methotrexate, and vinblastine; carboplatin, epirubicin, methotrexate, and vinblastine; and paclitaxel, gemcitabine, and carboplatin have been studied but are not widely used.[20-23]

Ongoing studies are evaluating new chemotherapy combinations.

Evidence (chemotherapy):

1. A prospective randomized trial that compared MVAC with cisplatin, cyclophosphamide, and doxorubicin demonstrated improved response rate and longer median survival (48 weeks vs. 36 weeks; P = .003) with the MVAC regimen.[25]
2. Results from a randomized trial that compared MVAC with single-agent cisplatin in advanced bladder cancer also showed a significant advantage with MVAC in both response rate and median survival (12.5 months vs. 8.2 months; P = .002).[26]
3. A multicenter, randomized, controlled trial compared CMV with methotrexate plus vinblastine without cisplatin in 214 patients. The relative risk of dying was 0.68 (95% CI, 0.51–0.90; P = .0065) in favor of CMV. The median survival was 7 months with CMV compared with 4.5 months for methotrexate plus vinblastine.[27]
4. The EORTC conducted another randomized trial that studied 263 patients with advanced bladder cancer and evaluated the efficacy of a high-dose intensity MVAC regimen given every 2 weeks with G-CSF compared with a classic MVAC regimen given every 4 weeks.[28]
   • Although there was no significant difference in OS at a median follow-up of 3.2 years (HR, 0.80; 95% CI, 0.60–1.06; P = .122), an update at a median follow-up of 7.3 years reported that the high-dose intensity MVAC regimen was associated with improved OS (HR, 0.76; 95% CI, 0.58–0.99; P = .042), with a 5-year survival rate of 22%, compared with 14% in patients treated with the classic MVAC regimen.
   • The high-dose intensity MVAC regimen was also associated with higher response rates (72% vs. 58%; P = .016), improved median PFS (9.5 months vs. 8.1 months; P = .017), and decreased neutropenic fever (10% vs. 26%, P < .001), although only 19% of patients treated with a classic MVAC regimen ever received G-CSF.[28][Level of evidence: 1iiA] An imbalance in baseline prognostic factors (i.e., visceral metastases were found in 37 patients randomly assigned to the high-dose MVAC regimen and 47 patients assigned to the classic MVAC regimen) may account, in part, for these results.
5. Gemcitabine plus cisplatin:
   • In a multicenter randomized phase III trial that compared GC with the MVAC regimen in 405 patients with advanced or metastatic bladder cancer, GC yielded response rates, time-to-progression, and OS (HR = 1.04; 95% CI, 0.82–1.32; P = .75) similar to MVAC, but GC had a better safety profile and was better tolerated than MVAC.
   • Although this study was not designed to show the equivalence of the two regimens, the similar efficacy and reduced toxic effects of GC make it a reasonable alternative in patients who may not tolerate the MVAC regimen.[29][Level of evidence: 1iiA]

Ongoing studies are evaluating new chemotherapy combinations.

Immunotherapy

Immunotherapy has emerged as a treatment alternative for patients with stage IV bladder cancer. Immune checkpoint inhibitors that have anti−programmed death-1 (PD-1) or anti−programmed death-ligand 1 (PD-L1) activity have been shown in clinical trials to have activity against urothelial carcinoma in patients who have previously been treated with or who are ineligible for platinum-based chemotherapy.[37-41] There are currently four different agents approved; however, pembrolizumab is the agent with the highest level of evidence and the greatest data in terms of survival.

Pembrolizumab

Pembrolizumab is a humanized monoclonal antibody that binds to PD-1. In patients previously treated with platinum-based chemotherapy, pembrolizumab has been shown to prolong OS compared with second-line chemotherapy. As a result, pembrolizumab has been approved by the U.S. Food and Drug Administration for patients with locally advanced or metastatic urothelial carcinoma who are cisplatin ineligible or whose disease has progressed after treatment with platinum-based chemotherapy.

Evidence (pembrolizumab):

1. In an open-label, international, randomized, controlled phase III trial (NCT02256436) of pembrolizumab (200 mg intravenously [IV] every 21 days) versus second-line chemotherapy (investigator’s choice of paclitaxel, docetaxel, or vinflunine) in patients whose disease had progressed after treatment with platinum-based chemotherapy, median OS was longer with pembrolizumab (10.3 months vs. 7.4 months; HR, 0.73; 95% CI, 0.59–0.91).[42]
   • In patients with a PD-L1 combined positive score of at least 10%, median OS was 8.0 months with pembrolizumab compared with 5.2 months of chemotherapy (HR, 0.57; 95% CI, 0.37–0.88).
   • The PFS rate at 12 months was 16.8% (95% CI, 12.3–22.0 months) in the pembrolizumab arm and 6.2% (95% CI, 3.3–10.2 months) in the chemotherapy arm.
   • The objective response rate was 21.1% in the pembrolizumab arm and 11.4% in the chemotherapy arm. Among those who responded, the median duration of response was longer than 18 months with pembrolizumab compared with a response of 4.3 months with chemotherapy.
   • Pembrolizumab was associated with a lower rate of treatment-related adverse events than was chemotherapy (60.9% vs. 90.2%) and a lower rate of high-grade adverse events (15.0% vs. 49.4%). The most common adverse events with pembrolizumab were pruritus, fatigue, nausea, diarrhea, and decreased appetite.[42][Level of evidence: 1iiA]
2. In a single-arm, phase II trial (NCT02335424) of pembrolizumab in 370 treatment-naïve, cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma, the overall response rate was 29%. In patients with a PD-L1 combined positive score of at least 10%, the overall response rate was 51%.[43]
   • Median duration of response had not been reached. Eighty-two percent of responses lasted at least 6 months.
   • Ten percent of patients had a serious treatment-related adverse event, and one patient died from treatment-related adverse events. The most common high-grade adverse events were fatigue (2%), elevated alkaline phosphatase (1%), colitis (1%), and muscle weakness (1%).[43][Level of evidence: 3iiiDiv]

Atezolizumab

Atezolizumab is a humanized monoclonal antibody that binds to PD-L1 and prevents it from binding to its receptors, PD-1 or B7-1. Clinical trials have reported that atezolizumab acts against urothelial carcinoma, but it has not shown prolonged OS or improved quality of life. The only randomized controlled trial testing atezolizumab reported no significant difference in OS compared with second-line chemotherapy.

Evidence (atezolizumab):

1. The IMvigor211 trial (NCT02302807) is a randomized, controlled trial that compared atezolizumab with second-line chemotherapy (docetaxel, paclitaxel, or vinflunine) in 931 patients with locally advanced or metastatic urothelial carcinoma who were previously treated with platinum-containing chemotherapy.[44] The trial design specified that OS would be primarily assessed in patients with tumors in which at least 5% of cells stained for PD-L1.
   • Median OS was 11.1 months for atezolizumab versus 10.6 months for chemotherapy in patients with at least 5% of tumor cells staining for PD-L1 (P = .41).[44][Level of evidence: 1iiA]
   • Response rates were also similar: 23% with atezolizumab and 22% with chemotherapy.
   • Patients receiving atezolizumab had a lower rate of high-grade toxicity (20% vs. 43%) and a lower rate of treatment discontinuation resulting from adverse events (7% vs. 18%).
2. In a multicenter, single-arm trial (NCT0108652) of atezolizumab (1,200 mg IV every 21 days) in 315 cisplatin-ineligible patients or patients who were previously treated with platinum-based chemotherapy and who had inoperable locally advanced or metastatic urothelial carcinoma, the following results were reported:[40][Level of evidence: 3iiiD]
   • The overall response rate was 15%.
   • With a median follow-up of 11.7 months, 38 of 45 responders (84%) had an ongoing response.
   • The response rate was 27% in those with PD-L1 expression of at least 5%, 10% in those with PD-L1 expression of 1% to 5%, and 8% in those with PD-L1 expression of less than 1%.
   • Grade 3 to 4 adverse events were reported in 16% of patients, and high-grade, immune-related adverse events were reported in 5% of patients.
3. Similarly, a study (NCT02108652) of 123 previously untreated patients with cisplatin-ineligible, locally advanced metastatic urothelial carcinoma who were treated with atezolizumab reported that at 17.2 months' median follow-up, the objective response rate was 23%, and 9% had complete responses.[41][Level of evidence: 3iiiD]
   • Of the 27 responses, 19 were ongoing at the time of data analysis. Median OS was 15.9 months.
   • High-grade adverse events were reported in 16% of patients, 8% of patients discontinued treatment because of the adverse events, and there was one treatment-related death.

Nivolumab

Nivolumab is a fully human immunoglobulin G4 PD-1 immune checkpoint inhibitor antibody that blocks interaction between PD-L1 and PD-L2 with PD-1. There are no published controlled trials and thus no data regarding whether nivolumab results in longer survival or improved quality of life.

Evidence (nivolumab):

1. In a multicenter trial (NCT01928394) of 86 patients with metastatic urothelial carcinoma whose disease progressed after platinum-based chemotherapy, patients were treated with nivolumab (3 mg/kg IV every 2 weeks).[39][Level of evidence: 2iD]
   • With a minimum follow-up of 9 months and a median follow-up of 15 months, 24% had an objective response, and 22% had grade 3 or 4 adverse events.
   • The most common adverse events were elevated lipase or amylase, fatigue, rash, dyspnea, lymphopenia, and neutropenia.
2. Another multicenter study (NCT02387996) of 270 patients with locally advanced or metastatic urothelial carcinoma that had progressed after treatment with platinum-based chemotherapy reported an objective response rate of 20%.[38][Level of evidence: 2iD]
   • When evaluated by PD-L1 expression, the objective response rate was 28% in those with PD-L1 expression of 5% or greater; 24% in those with PD-L1 expression of 1% or greater; and 16% in those with PD-L1 expression of less than 1%.
   • Grade 3 to 4 adverse events were reported in 18% of patients.
   • There were three treatment-related deaths.

Avelumab

Avelumab is a monoclonal anti–PD-L1 antibody that has shown activity against urothelial carcinoma. There are no published controlled trials and no data demonstrating either longer survival or improved quality of life with this agent.

Evidence (avelumab):

1. A study (NCT01772004) of avelumab (10 mg/kg IV every 14 days) in 249 patients with metastatic urothelial carcinoma who had progressed after treatment with platinum-based chemotherapy reported the following results:[45,46][Level of evidence: 3iiiDiv]
   • Among the 161 patients with at least 6 months of follow-up, the overall response rate was 17%, and response was ongoing in 23 of 28 responders with a median follow-up of 7.3 months. Six percent of the patients had a complete response.
   • The overall response rate was 25.0% in patients with at least 5% of tumor cells staining for PD-L1 and 14.7% for those with less than 5% PD-L1 positivity.
   • Median PFS was 6.3 weeks; 23% of the patients were progression free at 24 weeks.
   • A treatment-related adverse event was reported in 66.7% of patients, including 8.4% of patients with high-grade adverse events. There was one treatment-related death from pneumonitis. High-grade immune-related adverse events were reported in 2.4% of patients.

Durvalumab

Durvalumab is an anti–PD-L1 monoclonal antibody that has shown activity against urothelial carcinoma. There are no published controlled trials and no data demonstrating either longer survival or improved quality of life with this agent.

Evidence (durvalumab):

1. The efficacy of durvalumab (10 mg/kg IV every 14 days) was assessed in a study (NCT01693562) of 191 patients with locally advanced or metastatic urothelial carcinoma whose disease had progressed while they were on chemotherapy or who were either ineligible for or unwilling to be treated with chemotherapy.[47][Level of evidence: 3iiiDiv]
   • With a median follow-up of 5.78 months, the overall response rate was 17.8%.
   • The response rate was 27.6% in patients with high expression of PD-L1 compared with 5.1% in patients with low or no PD-L1 expression.
   • High-grade adverse events were reported in 6.8% of patients, including 2.1% with high-grade immune-mediated adverse events.

EBRT for palliation

Definitive radiation therapy with or without concurrent chemotherapy, evaluated mainly in patients with locally advanced (T2–T4) disease, appears to have minimal curative potential in patients with regional lymph node metastases.

Urinary diversion or cystectomy for palliation

Urinary diversion may be indicated, not only for palliation of urinary symptoms, but also for preservation of renal function in candidates for chemotherapy.

Treatment Options Under Clinical Evaluation for Patients With Any T, Any N, M1 Disease

Prognosis is poor in patients with stage IV disease and consideration of entry into a clinical trial is appropriate.

Other chemotherapy regimens appear to be active in the treatment of metastatic disease. Chemotherapy agents that have shown activity in metastatic bladder cancer include paclitaxel, docetaxel, ifosfamide, gallium nitrate, and pemetrexed.[48,49][Level of evidence: 3iiiDiv]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

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2. Kachnic LA, Kaufman DS, Heney NM, et al.: Bladder preservation by combined modality therapy for invasive bladder cancer. J Clin Oncol 15 (3): 1022-9, 1997. [PUBMED Abstract]
3. Tester W, Porter A, Asbell S, et al.: Combined modality program with possible organ preservation for invasive bladder carcinoma: results of RTOG protocol 85-12. Int J Radiat Oncol Biol Phys 25 (5): 783-90, 1993. [PUBMED Abstract]
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5. Skinner DG, Daniels JR, Russell CA, et al.: The role of adjuvant chemotherapy following cystectomy for invasive bladder cancer: a prospective comparative trial. J Urol 145 (3): 459-64; discussion 464-7, 1991. [PUBMED Abstract]
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7. von der Maase H, Sengelov L, Roberts JT, et al.: Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol 23 (21): 4602-8, 2005. [PUBMED Abstract]
8. Vaishampayan UN, Faulkner JR, Small EJ, et al.: Phase II trial of carboplatin and paclitaxel in cisplatin-pretreated advanced transitional cell carcinoma: a Southwest Oncology Group study. Cancer 104 (8): 1627-32, 2005. [PUBMED Abstract]
9. Carles J, Nogué M: Gemcitabine/carboplatin in advanced urothelial cancer. Semin Oncol 28 (3 Suppl 10): 19-24, 2001. [PUBMED Abstract]
10. Linardou H, Aravantinos G, Efstathiou E, et al.: Gemcitabine and carboplatin combination as first-line treatment in elderly patients and those unfit for cisplatin-based chemotherapy with advanced bladder carcinoma: Phase II study of the Hellenic Co-operative Oncology Group. Urology 64 (3): 479-84, 2004. [PUBMED Abstract]
11. De Santis M, Bellmunt J, Mead G, et al.: Randomized phase II/III trial assessing gemcitabine/ carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer "unfit" for cisplatin-based chemotherapy: phase II--results of EORTC study 30986. J Clin Oncol 27 (33): 5634-9, 2009. [PUBMED Abstract]
12. Sternberg CN, Calabrò F, Pizzocaro G, et al.: Chemotherapy with an every-2-week regimen of gemcitabine and paclitaxel in patients with transitional cell carcinoma who have received prior cisplatin-based therapy. Cancer 92 (12): 2993-8, 2001. [PUBMED Abstract]
13. Kaufman DS, Carducci MA, Kuzel TM, et al.: A multi-institutional phase II trial of gemcitabine plus paclitaxel in patients with locally advanced or metastatic urothelial cancer. Urol Oncol 22 (5): 393-7, 2004 Sep-Oct. [PUBMED Abstract]
14. Calabrò F, Lorusso V, Rosati G, et al.: Gemcitabine and paclitaxel every 2 weeks in patients with previously untreated urothelial carcinoma. Cancer 115 (12): 2652-9, 2009. [PUBMED Abstract]
15. Stadler WM, Kuzel T, Roth B, et al.: Phase II study of single-agent gemcitabine in previously untreated patients with metastatic urothelial cancer. J Clin Oncol 15 (11): 3394-8, 1997. [PUBMED Abstract]
16. Lorusso V, Pollera CF, Antimi M, et al.: A phase II study of gemcitabine in patients with transitional cell carcinoma of the urinary tract previously treated with platinum. Italian Co-operative Group on Bladder Cancer. Eur J Cancer 34 (8): 1208-12, 1998. [PUBMED Abstract]
17. Roth BJ, Dreicer R, Einhorn LH, et al.: Significant activity of paclitaxel in advanced transitional-cell carcinoma of the urothelium: a phase II trial of the Eastern Cooperative Oncology Group. J Clin Oncol 12 (11): 2264-70, 1994. [PUBMED Abstract]
18. Dreicer R, Gustin DM, See WA, et al.: Paclitaxel in advanced urothelial carcinoma: its role in patients with renal insufficiency and as salvage therapy. J Urol 156 (5): 1606-8, 1996. [PUBMED Abstract]
19. Vaughn DJ, Broome CM, Hussain M, et al.: Phase II trial of weekly paclitaxel in patients with previously treated advanced urothelial cancer. J Clin Oncol 20 (4): 937-40, 2002. [PUBMED Abstract]
20. Bellmunt J, Albanell J, Gallego OS, et al.: Carboplatin, methotrexate, and vinblastine in patients with bladder cancer who were ineligible for cisplatin-based chemotherapy. Cancer 70 (7): 1974-9, 1992. [PUBMED Abstract]
21. Bellmunt J, Ribas A, Albanell J, et al.: M-CAVI, a neoadjuvant carboplatin-based regimen for the treatment of T2-4N0M0 carcinoma of the bladder. Am J Clin Oncol 19 (4): 344-8, 1996. [PUBMED Abstract]
22. Skarlos DV, Aravantinos G, Linardou E, et al.: Chemotherapy with methotrexate, vinblastine, epirubicin and carboplatin (Carbo-MVE) in transitional cell urothelial cancer. A Hellenic Co-Operative Oncology Group study. Eur Urol 31 (4): 420-7, 1997. [PUBMED Abstract]
23. Hainsworth JD, Meluch AA, Litchy S, et al.: Paclitaxel, carboplatin, and gemcitabine in the treatment of patients with advanced transitional cell carcinoma of the urothelium. Cancer 103 (11): 2298-303, 2005. [PUBMED Abstract]
24. Bamias A, Aravantinos G, Deliveliotis C, et al.: Docetaxel and cisplatin with granulocyte colony-stimulating factor (G-CSF) versus MVAC with G-CSF in advanced urothelial carcinoma: a multicenter, randomized, phase III study from the Hellenic Cooperative Oncology Group. J Clin Oncol 22 (2): 220-8, 2004. [PUBMED Abstract]
25. Logothetis CJ, Dexeus FH, Finn L, et al.: A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors. J Clin Oncol 8 (6): 1050-5, 1990. [PUBMED Abstract]
26. Loehrer PJ Sr, Einhorn LH, Elson PJ, et al.: A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol 10 (7): 1066-73, 1992. [PUBMED Abstract]
27. Mead GM, Russell M, Clark P, et al.: A randomized trial comparing methotrexate and vinblastine (MV) with cisplatin, methotrexate and vinblastine (CMV) in advanced transitional cell carcinoma: results and a report on prognostic factors in a Medical Research Council study. MRC Advanced Bladder Cancer Working Party. Br J Cancer 78 (8): 1067-75, 1998. [PUBMED Abstract]
28. Sternberg CN, de Mulder P, Schornagel JH, et al.: Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer 42 (1): 50-4, 2006. [PUBMED Abstract]
29. von der Maase H, Hansen SW, Roberts JT, et al.: Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol 18 (17): 3068-77, 2000. [PUBMED Abstract]
30. Konety BR, Joslyn SA, O'Donnell MA: Extent of pelvic lymphadenectomy and its impact on outcome in patients diagnosed with bladder cancer: analysis of data from the Surveillance, Epidemiology and End Results Program data base. J Urol 169 (3): 946-50, 2003. [PUBMED Abstract]
31. Thrasher JB, Crawford ED: Current management of invasive and metastatic transitional cell carcinoma of the bladder. J Urol 149 (5): 957-72, 1993. [PUBMED Abstract]
32. Grossman HB, Natale RB, Tangen CM, et al.: Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 349 (9): 859-66, 2003. [PUBMED Abstract]
33. Jahnson S, Pedersen J, Westman G: Bladder carcinoma--a 20-year review of radical irradiation therapy. Radiother Oncol 22 (2): 111-7, 1991. [PUBMED Abstract]
34. Coppin CM, Gospodarowicz MK, James K, et al.: Improved local control of invasive bladder cancer by concurrent cisplatin and preoperative or definitive radiation. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 14 (11): 2901-7, 1996. [PUBMED Abstract]
35. Shipley WU, Winter KA, Kaufman DS, et al.: Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03. J Clin Oncol 16 (11): 3576-83, 1998. [PUBMED Abstract]
36. James ND, Hussain SA, Hall E, et al.: Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med 366 (16): 1477-88, 2012. [PUBMED Abstract]
37. Plimack ER, Bellmunt J, Gupta S, et al.: Safety and activity of pembrolizumab in patients with locally advanced or metastatic urothelial cancer (KEYNOTE-012): a non-randomised, open-label, phase 1b study. Lancet Oncol 18 (2): 212-220, 2017. [PUBMED Abstract]
38. Sharma P, Retz M, Siefker-Radtke A, et al.: Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol 18 (3): 312-322, 2017. [PUBMED Abstract]
39. Sharma P, Callahan MK, Bono P, et al.: Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): a multicentre, open-label, two-stage, multi-arm, phase 1/2 trial. Lancet Oncol 17 (11): 1590-1598, 2016. [PUBMED Abstract]
40. Rosenberg JE, Hoffman-Censits J, Powles T, et al.: Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 387 (10031): 1909-20, 2016. [PUBMED Abstract]
41. Balar AV, Galsky MD, Rosenberg JE, et al.: Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet 389 (10064): 67-76, 2017. [PUBMED Abstract]
42. Bellmunt J, de Wit R, Vaughn DJ, et al.: Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med 376 (11): 1015-1026, 2017. [PUBMED Abstract]
43. Balar AV, Castellano D, O'Donnell PH, et al.: First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol 18 (11): 1483-1492, 2017. [PUBMED Abstract]
44. Powles T, Durán I, van der Heijden MS, et al.: Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet 391 (10122): 748-757, 2018. [PUBMED Abstract]
45. Apolo AB, Ellerton JA, Infante JR, et al.: Updated efficacy and safety of avelumab in metastatic urothelial carcinoma (mUC): pooled analysis from 2 cohorts of the phase 1b Javelin solid tumor study. [Abstract] J Clin Oncol 35 (Suppl 15): A-4529, 2017.
46. Patel MR, Ellerton J, Infante JR, et al.: Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol 19 (1): 51-64, 2018. [PUBMED Abstract]
47. Powles T, O'Donnell PH, Massard C, et al.: Efficacy and Safety of Durvalumab in Locally Advanced or Metastatic Urothelial Carcinoma: Updated Results From a Phase 1/2 Open-label Study. JAMA Oncol 3 (9): e172411, 2017. [PUBMED Abstract]
48. Raghavan D, Huben R: Management of bladder cancer. Curr Probl Cancer 19 (1): 1-64, 1995 Jan-Feb. [PUBMED Abstract]
49. Sweeney CJ, Roth BJ, Kabbinavar FF, et al.: Phase II study of pemetrexed for second-line treatment of transitional cell cancer of the urothelium. J Clin Oncol 24 (21): 3451-7, 2006. [PUBMED Abstract]

Recurrent Bladder Cancer Treatment

In This Section

• Treatment Options for Recurrent Bladder Cancer
  • Combination chemotherapy
  • Immunotherapy
  • Surgery for new superficial or localized tumors
  • Palliative therapy
  • Clinical trials
• Current Clinical Trials

The prognosis for any patient with progressive or recurrent invasive bladder cancer is generally poor. Management of recurrence depends on previous therapy, sites of recurrence, and individual patient considerations.

Treatment Options for Recurrent Bladder Cancer

Treatment options for patients with recurrent bladder cancer include the following:

1. Combination chemotherapy.
2. Immunotherapy.
3. Surgery for new superficial or localized tumors.
4. Palliative therapy.
5. Clinical trials.

Combination chemotherapy

Patients who have not received previous chemotherapy for urothelial carcinoma should be considered for chemotherapy as described above for stage IV disease.

In patients with recurrent transitional cell carcinoma, combination chemotherapy has produced high response rates, with occasional complete responses seen.[1,2]

Evidence (combination chemotherapy):

1. Results from a randomized trial that compared methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) with single-agent cisplatin in patients with advanced bladder cancer show a significant advantage with MVAC in both response rate and median survival.[3] The overall response rate with MVAC in this cooperative group trial was 39%.
2. Results from a randomized trial that compared MVAC with cisplatin, cyclophosphamide, and doxorubicin in 110 patients reported longer overall survival (OS) with MVAC (median survival 48.3 weeks vs. 36.1 weeks; P = .0003).[4]
3. Results from a randomized trial that compared cisplatin, methotrexate, and vinblastine (CMV) with methotrexate plus vinblastine reported longer OS with CMV (median survival 7 months vs. 4.5 months; hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.41–0.73; P = .0001).[5]
4. In a multicenter, randomized, phase III trial that compared the combination of gemcitabine plus cisplatin (GC) with the MVAC regimen in 405 patients with advanced or metastatic bladder cancer, GC yielded response rates, time-to-progression, and OS (HR, 1.04; 95% CI, 0.82–1.32; P = .75) similar to MVAC, but GC had a better safety profile and was better tolerated than MVAC. Although this study was not designed to show the equivalence of the two regimens, the similar efficacy and reduced toxic effects of GC make it a reasonable alternative in patients who may not tolerate the MVAC regimen.[6][Level of evidence: 1iiA]
5. Other chemotherapy regimens that have shown activity in metastatic bladder cancer include single-agent paclitaxel, single-agent gemcitabine, single-agent pemetrexed, carboplatin combined with either gemcitabine or paclitaxel, and gemcitabine combined with paclitaxel. There are no phase III trials demonstrating a survival or quality-of-life benefit from second-line chemotherapy.[7-14]

Immunotherapy

Immunotherapy has emerged as a treatment alternative for patients with recurrent bladder cancer. Immune checkpoint inhibitors that have anti−programmed death-1 (PD-1) or anti−programmed death-ligand 1 (PD-L1) activity have been shown in clinical trials to have activity against urothelial carcinoma in patients who have previously been treated with or who are ineligible for cisplatin-based chemotherapy.[15-19] There are currently four different agents approved; however, pembrolizumab is the agent with the highest level of evidence and the greatest data in terms of survival.

Pembrolizumab

Pembrolizumab is a humanized monoclonal antibody that binds to PD-1. In patients previously treated with platinum-based chemotherapy, pembrolizumab has been shown to prolong OS compared with second-line chemotherapy. As a result, pembrolizumab has been approved by the U.S. Food and Drug Administration for patients with locally advanced or metastatic urothelial carcinoma who are either cisplatin-ineligible or whose disease has progressed after treatment with platinum-based chemotherapy.

Evidence (pembrolizumab):

1. In an open-label, international, randomized, controlled phase III trial (NCT02256436) of pembrolizumab (200 mg intravenously [IV] every 21 days) versus second-line chemotherapy (investigator’s choice of paclitaxel, docetaxel, or vinflunine) in patients whose disease progressed after treatment with platinum-based chemotherapy, median OS was longer with pembrolizumab (10.3 months vs.7.4 months; HR, 0.73; 95% CI, 0.59–0.91).[20]
   • In patients with a PD-L1 combined positive score of at least 10%, median OS was 8.0 months with pembrolizumab compared with 5.2 months of chemotherapy (HR, 0.57; 95% CI, 0.37–0.88).
   • PFS at 12 months was 16.8% (95% CI, 12.3–22.0 months) in the pembrolizumab arm and 6.2% (95% CI, 3.3–10.2 months) in the chemotherapy arm.
   • The objective response rate was 21.1% in the pembrolizumab arm and 11.4% in the chemotherapy arm. Among those who responded, the median duration of response was longer than 18 months with pembrolizumab compared with a response of 4.3 months with chemotherapy.
   • Pembrolizumab was associated with a lower rate of treatment-related adverse events than was chemotherapy (60.9% vs. 90.2%) and a lower rate of high-grade adverse events (15.0% vs. 49.4%). The most common adverse events with pembrolizumab were pruritus, fatigue, nausea, diarrhea, and decreased appetite.[20][Level of evidence: 1iiA]
2. In a single-arm phase II trial (NCT02335424) of pembrolizumab in 370 treatment-naïve, cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma, the overall response rate was 29%. In patients with a PD-L1 combined positive score of at least 10%, the overall response rate was 51%.[21]
   • Median duration of response had not been reached. Eighty-two percent of responses lasted at least 6 months.
   • Ten percent of patients had a serious treatment-related adverse event, and one patient died from treatment-related adverse events. The most common high-grade adverse events were fatigue (2%), elevated alkaline phosphatase (1%), colitis (1%), and muscle weakness (1%).[21][Level of evidence: 3iiiDiv]

Atezolizumab

Atezolizumab is a humanized monoclonal antibody that binds to PD-L1 and prevents it from binding to its receptors PD-1 or B7-1. Clinical trials have reported that atezolizumab acts against urothelial carcinoma, but it has not shown prolonged OS or improved quality of life. The only randomized controlled trial testing atezolizumab reported no significant difference in OS compared with second-line chemotherapy.

Evidence (atezolizumab):

1. The IMvigor211 trial (NCT02302807) is a randomized controlled trial that compared atezolizumab with second-line chemotherapy (docetaxel, paclitaxel, or vinflunine) in 931 patients with locally advanced or metastatic urothelial carcinoma who were previously treated with platinum-containing chemotherapy.[22] The trial design specified that OS would be primarily assessed in patients with tumors in which at least 5% of cells stained for PD-L1.
   • Median OS was 11.1 months for atezolizumab versus 10.6 months for chemotherapy in patients with at least 5% of tumor cells staining for PD-L1 (P = .41).[22][Level of evidence: 1iiA]
   • Response rates were also similar: 23% with atezolizumab and 22% with chemotherapy.
   • Patients receiving atezolizumab had a lower rate of high-grade toxicity (20% vs. 43%) and a lower rate of treatment discontinuation resulting from adverse events (7% vs. 18%).
2. In a multicenter, single-arm trial (NCT0108652) of atezolizumab (1,200 mg IV every 21 days) in 315 cisplatin-ineligible patients or patients who were previously treated with platinum-based chemotherapy and who had inoperable locally advanced or metastatic urothelial carcinoma, the following results were reported:[18][Level of evidence: 3iiiD]
   • The overall response rate was 15%.
   • With a median follow-up of 11.7 months, 38 of 45 responders (84%) had an ongoing response.
   • The response rate was 27% in those with PD-L1 expression of at least 5%, 10% in those with PD-L1 expression of 1% to 5%, and 8% in those with PD-L1 expression of less than 1%.
   • Grade 3/4 adverse events were reported in 16% of patients, and high-grade immune-related adverse events were reported in 5% of patients.
3. Similarly, a study (NCT02108652) of 123 previously untreated patients with cisplatin-ineligible, locally advanced metastatic urothelial carcinoma who were treated with atezolizumab reported that at 17.2 months' median follow-up, the objective response rate was 23%, and 9% had complete responses.[19][Level of evidence: 3iiiD]
   • Of the 27 responses, 19 were ongoing at the time of data analysis. Median OS was 15.9 months.
   • High-grade adverse events were reported in 16% of patients, 8% of patients discontinued treatment because of the adverse events, and there was one treatment-related death.

Nivolumab

Nivolumab is a fully human immunoglobulin G4 PD-1 immune checkpoint inhibitor antibody that blocks interaction between PD-L1 and PD-L2 with PD-1. There are no published controlled trials and thus no data regarding whether nivolumab results in longer survival or improved quality of life.

Evidence (nivolumab):

1. In a multicenter trial (NCT01928394) of 86 patients with metastatic urothelial carcinoma whose disease progressed after platinum-based chemotherapy, patients were treated with nivolumab (3 mg/kg IV every 2 weeks).[17][Level of evidence: 2iD]
   • With a minimum follow-up of 9 months and a median follow-up of 15 months, 24% had an objective response, and 22% had grade 3 or 4 adverse events.
   • The most common adverse events were elevated lipase or amylase, fatigue, rash, dyspnea, lymphopenia, and neutropenia.
2. Another multicenter study (NCT02387996) of 270 patients with locally advanced or metastatic urothelial carcinoma that had progressed after treatment with platinum-based chemotherapy reported an objective response rate of 20%.[16][Level of evidence: 2iD]
   • When evaluated by PD-L1 expression, the objective response rate was 28% in those with PD-L1 expression of 5% or greater; 24% in those with PD-L1 expression of 1% or greater; and 16% in those with PD-L1 expression of less than 1%.
   • Grade 3 to 4 adverse events were reported in 18% of patients.
   • There were three treatment-related deaths.

Avelumab

Avelumab is a monoclonal anti–PD-L1 antibody that has shown activity against urothelial carcinoma. There are no published controlled trials and no data demonstrating either longer survival or improved quality of life with this agent.

Evidence (avelumab):

1. A study (NCT01772004) of avelumab (10 mg/kg IV every 14 days) in 249 patients with metastatic urothelial carcinoma who had progressed after treatment with platinum-based chemotherapy reported the following results:[23,24][Level of evidence: 3iiiDiv]
   • Among the 161 patients with at least 6 months of follow-up, the overall response rate was 17%, and response was ongoing in 23 of 28 responders with a median follow-up of 7.3 months. Six percent of the patients had a complete response.
   • The overall response rate was 25.0% in patients with at least 5% of tumor cells staining for PD-L1 and 14.7% for those with less than 5% PD-L1 positivity.
   • Median progression-free survival was 6.3 weeks; 23% of the patients were progression free at 24 weeks.
   • A treatment-related adverse event was reported in 66.7% of patients, including 8.4% of patients with high-grade adverse events. There was one treatment-related death from pneumonitis. High-grade immune-related adverse events were reported in 2.4% of patients.

Durvalumab

Durvalumab is an anti–PD-L1 monoclonal antibody that has shown activity against urothelial carcinoma. There are no published controlled trials and no data demonstrating either longer survival or improved quality of life with this agent.

Evidence (durvalumab):

1. The efficacy of durvalumab (10 mg/kg IV every 14 days) was assessed in a study (NCT01693562) of 191 patients with locally advanced or metastatic urothelial carcinoma whose disease had progressed while they were on chemotherapy or who were either ineligible for or unwilling to be treated with chemotherapy.[25][Level of evidence: 3iiiDiv]
   • With a median follow-up of 5.78 months, the overall response rate was 17.8%.
   • The response rate was 27.6% in patients with high expression of PD-L1 compared with 5.1% in patients with low or no PD-L1 expression.
   • High-grade adverse events were reported in 6.8% of patients, including 2.1% with high-grade immune-mediated adverse events.

Surgery for new superficial or localized tumors

Treatment of new superficial or locally invasive tumors that develop in the setting of previous conservative therapy for superficial bladder neoplasia has been discussed earlier in stage I in this summary.

Palliative therapy

Palliative radiation therapy should be considered for patients with symptomatic tumors.

Clinical trials

Recurrent or progressive disease in distant sites or after definitive local therapy has an extremely poor prognosis, and clinical trials should be considered whenever possible.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

1. Sternberg CN, Yagoda A, Scher HI, et al.: Methotrexate, vinblastine, doxorubicin, and cisplatin for advanced transitional cell carcinoma of the urothelium. Efficacy and patterns of response and relapse. Cancer 64 (12): 2448-58, 1989. [PUBMED Abstract]
2. Harker WG, Meyers FJ, Freiha FS, et al.: Cisplatin, methotrexate, and vinblastine (CMV): an effective chemotherapy regimen for metastatic transitional cell carcinoma of the urinary tract. A Northern California Oncology Group study. J Clin Oncol 3 (11): 1463-70, 1985. [PUBMED Abstract]
3. Loehrer PJ Sr, Einhorn LH, Elson PJ, et al.: A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol 10 (7): 1066-73, 1992. [PUBMED Abstract]
4. Logothetis CJ, Dexeus FH, Finn L, et al.: A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors. J Clin Oncol 8 (6): 1050-5, 1990. [PUBMED Abstract]
5. Mead GM, Russell M, Clark P, et al.: A randomized trial comparing methotrexate and vinblastine (MV) with cisplatin, methotrexate and vinblastine (CMV) in advanced transitional cell carcinoma: results and a report on prognostic factors in a Medical Research Council study. MRC Advanced Bladder Cancer Working Party. Br J Cancer 78 (8): 1067-75, 1998. [PUBMED Abstract]
6. von der Maase H, Hansen SW, Roberts JT, et al.: Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol 18 (17): 3068-77, 2000. [PUBMED Abstract]
7. Roth BJ: Preliminary experience with paclitaxel in advanced bladder cancer. Semin Oncol 22 (3 Suppl 6): 1-5, 1995. [PUBMED Abstract]
8. Witte RS, Elson P, Bono B, et al.: Eastern Cooperative Oncology Group phase II trial of ifosfamide in the treatment of previously treated advanced urothelial carcinoma. J Clin Oncol 15 (2): 589-93, 1997. [PUBMED Abstract]
9. Einhorn LH, Roth BJ, Ansari R, et al.: Phase II trial of vinblastine, ifosfamide, and gallium combination chemotherapy in metastatic urothelial carcinoma. J Clin Oncol 12 (11): 2271-6, 1994. [PUBMED Abstract]
10. Pollera CF, Ceribelli A, Crecco M, et al.: Weekly gemcitabine in advanced bladder cancer: a preliminary report from a phase I study. Ann Oncol 5 (2): 182-4, 1994. [PUBMED Abstract]
11. Seidman AD, Scher HI, Heinemann MH, et al.: Continuous infusion gallium nitrate for patients with advanced refractory urothelial tract tumors. Cancer 68 (12): 2561-5, 1991. [PUBMED Abstract]
12. Roth BJ: Ifosfamide in the treatment of bladder cancer. Semin Oncol 23 (3 Suppl 6): 50-5, 1996. [PUBMED Abstract]
13. Bajorin DF: Paclitaxel in the treatment of advanced urothelial cancer. Oncology (Huntingt) 14 (1): 43-52, 57; discussion 58, 61-2, 2000. [PUBMED Abstract]
14. Sweeney CJ, Roth BJ, Kabbinavar FF, et al.: Phase II study of pemetrexed for second-line treatment of transitional cell cancer of the urothelium. J Clin Oncol 24 (21): 3451-7, 2006. [PUBMED Abstract]
15. Plimack ER, Bellmunt J, Gupta S, et al.: Safety and activity of pembrolizumab in patients with locally advanced or metastatic urothelial cancer (KEYNOTE-012): a non-randomised, open-label, phase 1b study. Lancet Oncol 18 (2): 212-220, 2017. [PUBMED Abstract]
16. Sharma P, Retz M, Siefker-Radtke A, et al.: Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol 18 (3): 312-322, 2017. [PUBMED Abstract]
17. Sharma P, Callahan MK, Bono P, et al.: Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): a multicentre, open-label, two-stage, multi-arm, phase 1/2 trial. Lancet Oncol 17 (11): 1590-1598, 2016. [PUBMED Abstract]
18. Rosenberg JE, Hoffman-Censits J, Powles T, et al.: Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 387 (10031): 1909-20, 2016. [PUBMED Abstract]
19. Balar AV, Galsky MD, Rosenberg JE, et al.: Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet 389 (10064): 67-76, 2017. [PUBMED Abstract]
20. Bellmunt J, de Wit R, Vaughn DJ, et al.: Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med 376 (11): 1015-1026, 2017. [PUBMED Abstract]
21. Balar AV, Castellano D, O'Donnell PH, et al.: First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol 18 (11): 1483-1492, 2017. [PUBMED Abstract]
22. Powles T, Durán I, van der Heijden MS, et al.: Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet 391 (10122): 748-757, 2018. [PUBMED Abstract]
23. Apolo AB, Ellerton JA, Infante JR, et al.: Updated efficacy and safety of avelumab in metastatic urothelial carcinoma (mUC): pooled analysis from 2 cohorts of the phase 1b Javelin solid tumor study. [Abstract] J Clin Oncol 35 (Suppl 15): A-4529, 2017.
24. Patel MR, Ellerton J, Infante JR, et al.: Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol 19 (1): 51-64, 2018. [PUBMED Abstract]
25. Powles T, O'Donnell PH, Massard C, et al.: Efficacy and Safety of Durvalumab in Locally Advanced or Metastatic Urothelial Carcinoma: Updated Results From a Phase 1/2 Open-label Study. JAMA Oncol 3 (9): e172411, 2017. [PUBMED Abstract]

Changes to This Summary (02/06/2019)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

General Information About Bladder Cancer

Updated statistics with estimated new cases and deaths for 2019 (cited American Cancer society as reference 1).

Stage IV Bladder Cancer Treatment

Added text to state that there are currently four different immune checkpoint inhibitors approved; however, pembrolizumab is the agent with the highest level of evidence and the greatest data in terms of survival.

Added text to state that clinical trials have reported that atezolizumab acts against urothelial carcinoma, but it has not shown prolonged overall survival (OS) or improved quality of life. The only randomized controlled trial testing atezolizumab reported no significant difference in OS compared with second-line chemotherapy.

Added Powles et al. as reference 44 and level of evidence 1iiA.

Added text to state that response rates were 23% with atezolizumab and 22% with chemotherapy.

Added text to state that patients receiving atezolizumab had a lower rate of high-grade toxicity and a lower rate of treatment discontinuation resulting from adverse events.

Revised text to include a study of avelumab in 249 patients with metastatic urothelial carcinoma who had progressed after treatment with platinum-based chemotherapy (cited Patel et al. as reference 46).

Revised text to state that among the 161 patients with at least 6 months of follow-up, the overall response rate was 17%, and response was ongoing in 23 of 28 responders with a median follow-up of 7.3 months. Added that 6% of the patients had a complete response.

Added text to state that median progression-free survival (PFS) was 6.3 weeks; 23% of the patients were progression free at 24 weeks.

Recurrent Bladder Cancer Treatment

Added text to state that there are currently four different immune checkpoint inhibitors; however, pembrolizumab is the agent with the highest level of evidence and the greatest data in terms of survival.

Added text to state that clinical trials have reported that atezolizumab acts against urothelial carcinoma, but it has not shown prolonged OS or improved quality of life. The only randomized controlled trial testing atezolizumab reported no significant difference in OS compared with second-line chemotherapy.

Added Powles et al. as reference 22 and level of evidence 1iiA.

Added text to state that response rates were 23% with atezolizumab and 22% with chemotherapy.

Added text to state that patients receiving atezolizumab had a lower rate of high-grade toxicity and a lower rate of treatment discontinuation resulting from adverse events.

Revised text to include a study of avelumab in 249 patients with metastatic urothelial carcinoma who had progressed after treatment with platinum-based chemotherapy (cited Patel et al. as reference 24).

Revised text to state that among the 161 patients with at least 6 months of follow-up, the overall response rate was 17%, and response was ongoing in 23 of 28 responders with a median follow-up of 7.3 months. Added that 6% of the patients had a complete response.

Added text to state that median PFS was 6.3 weeks; 23% of the patients were progression free at 24 weeks.

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of bladder cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewer for Bladder Cancer Treatment is:

• Timothy Gilligan, MD (Cleveland Clinic Taussig Cancer Institute)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Bladder Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/bladder/hp/bladder-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389399]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

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Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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• Updated: January 17, 2019